Cerebrum

In 1971, reporter James Reston of the New York Times reported he had undergone emergency abdominal surgery in China with acupuncture as the only anesthetic, awakening in the United States a burgeoning of interest in this 4,000-year-old healing art. Today, more than 40 percent of physicians refer patients for acupuncture treatments, yet the practice is still fraught with mystery and controversy.

Cardiologist John Longhurst, former chairman of the department of medicine at the University of California, Irvine, initially was as skeptical as anyone, but he has seen in his own laboratory evidence that acupuncture works—not only for pain but for problems such as high blood pressure and heart disease. As the ancient brain science called acupuncture meets the rigorous analysis of Western medicine, he says, some complicated philosophy and research questions must be answered before we can fully take advantage of acupuncture’s unique capabilities.

More and more Americans are seeking their health care outside mainstream Western medicine, as an alternative or in addition to it. People now make 600 million visits a year for these other medical therapies, including acupuncture, and spend $30 billion out-of-pocket for them.1 Not surprisingly, some physicians have chosen to integrate alternative therapies into their practices. More than 15 percent of American and European physicians practice acupuncture; half of all physicians believe it is effective for certain conditions; and 40 percent refer patients for it. There are acupuncture examining and licensing boards in 35-plus states; more states introduced legislation in 2001 to regulate acupuncture. Insurance companies, once loath to reimburse for the procedure, now often do.

If it is clear that acceptance of acupuncture is growing not only among the public but in the medical community, it is just as clear that acupuncture is still controversial. Only now is it undergoing the rigorous analytical tests of Western medicine. As it does, we are learning more about how it works, where it can be uniquely helpful, and how to see it within the context of brain science.

Ten years ago I knew next to nothing about acupuncture. Then, in 1992, on a trip to the People’s Republic of China, I was approached by Shanghai Medical University professor Peng Li about doing collaborative research on it. Skeptical, I ﬁrmly declined his invitation, imagining that acupuncture was a folk medicine—perhaps one that functioned as a placebo. Professor Li and I continued to talk, however, and three years later I agreed to work with him. Since then, I have seen in my own laboratory evidence that acupuncture does work—not only to relieve pain but also as a possible treatment for some of the complex problems of cardiovascular disease. It is time to ﬁnd out how we can beneﬁt from this ancient science.

A 4,000-YEAR MEDICAL TRADITION

Acupuncture’s roots reach back to China’s Han dynasty when, during the reign of the Yellow Emperor (2697 B.C.), we ﬁnd the ﬁrst reference to treating maladies by stimulating regions on the body’s surface with needles. The earliest needles were made of stone; later, they were made of wood or bamboo and, much more recently, of metal. In the four millennia since acupuncture was invented, it has grown into an empirically derived science, incorporated into what today is called Traditional Chinese Medicine (TCM)—itself ﬁrst described in 206 B.C. in the Yellow Emperor’s Inner Classic.

Acupuncture’s roots reach back to China’s Han dynasty when, during the reign of the Yellow Emperor (2697 B.C.), we ﬁnd the ﬁrst reference to treating maladies by stimulating regions on the body’s surface with needles.

Acupuncture is based on a theory of meridians, or energy channels, through which a form of energy called Qi (pronounced “chee”) is thought to circulate to the body’s major organs. Along these meridians, Chinese physicians have marked out a series of precise acupuncture points or acupoints. There are 12 principal meridians, which are bilaterally symmetrical; eight subsidiary meridians; and several hundred acupoints along them that can be stimulated to treat different conditions.

The Chinese schema of the organ system includes the heart and pericardium (the “heart constrictor”), the liver, the lungs, the kidneys, the spleen (the Yin organs); and the stomach, large and small intestines, bladder, gallbladder, and tri-heater or triple burner (the Yang organs). Although each organ (except the tri-heater) appears to have a Western counterpart, the Chinese names of the organs do not precisely correspond to the Western anatomical descriptions. According to TCM, under normal, harmonious conditions, Yin and Yang—two opposing forces expressing (among other qualities) cold, dark, moist, and calm (Yin) or heat, light, dry, and activity (Yang)—are in balance. When disease occurs, the Qi becomes either deﬁcient (Yin predominating) or exaggerated (Yang predominating). Stimulation of the appropriate acupoint is required to reestablish the normal balance of energy ﬂow.

To ascertain whether the energy ﬂow is adequate, depleted, or excessive—and precisely how—the TCM physician uses diagnostic techniques such as visually inspecting the patient and asking questions, listening to the voice and breathing, smelling the breath and urine, examining special Chinese pulses at the wrists, and inspecting the tongue. Then, if indicated, the physician stimulates the acupoint at one or more locations to restore energy balance. Techniques for stimulation include acupuncture (using a needle), acupressure (using ﬁnger pressure), electroacupuncture (EA), and moxibustion (localized heating of an acupoint, most commonly by burning leaves of the herbs Artemesia vulgaris or Artemesia selengensis).

For centuries, this therapy remained the province of Eastern cultures, but as trade and communication opened up between East and West and immigration from the East to America and Europe swelled, TCM (and acupuncture in particular) spread around the world.

MAPPING ACUPUNCTURE ONTO WESTERN NEUROSCIENCE

Can we put this ancient therapy into the framework of modern Western anatomy, physiology, and medicine? Does it “map” onto our concepts of the nervous system?

Scientists have discovered that many acupuncture meridians are located over our major neural pathways. Stimulation, such as acupuncture or acupressure, can activate the underlying nerve ﬁbers—speciﬁcally, our ﬁnely myelinated and unmyelinated sensory nerve ﬁbers. This leads to heightened activity in certain regions of the brain, including the hypothalamus, midbrain, and medulla.2 Experiments using low-frequency, low-intensity electroacupuncture suggest that this stimulation triggers the release of naturally occurring opioids—our body’s own powerful painkillers—including endorphins and enkephalins, and possibly also nociceptin.

A part of the hypothalamus called the arcuate nucleus is especially important because it is a source of opioid peptides for other regions, among them the ventral lateral periaqueductal gray area in the midbrain. A closely related area of the midbrain, the dorsal lateral periaductal gray area, has been linked to our ﬁght-or-ﬂight response—the cardiovascular system’s reaction to danger and stress. These periaqueductal gray areas are connected to the rostral ventral lateral medulla, the area of our medulla that is the source of many nerve cells that project to our spinal cord and, through the sympathetic nerves, eventually to our cardiovascular system. Nor is this list of areas of the nervous system affected by acupuncture complete. For example, there are spinal regions also under the inﬂuence of the opioid system; it is likely that acupuncture affects them, too.

Acupuncture meridians, then, may be surface maps that direct access to our body’s underlying neural pathways. The ﬂow of energy, or Qi, may be related to neuronal trafﬁc and signal processing in the peripheral and central nervous systems. Acupuncture sends signals through ﬁne sensory nerves to a number of regions in the hindbrain, which in turn release opioids and opioid-like neurochemicals that can inhibit the signals from the autonomic nervous system to the heart and blood vessels. Thus acupuncture may affect distant organs by activating regions in the brain associated with pain, with alerting reactions, and with cardiovascular regulation. The opioid system in the brain and spinal cord is one such mechanism that appears to play a role in responses to acupuncture.

WHERE ACUPUNCTURE CAN HELP

We in the West are just beginning to ﬁgure out not only how, but where, acupuncture works. You may have heard reports that the Chinese use acupuncture instead of anesthesia during surgery.3 Actually, most anesthesiologists in China today use acupuncture as an adjunct in surgery, a way to reduce the amount of traditional injectable or inhaled anesthetics that is needed. This use of acupuncture is associated with very few side effects and, because it reduces the concentrations of pharmacological agents, lowers the danger of complications.

Beyond this, in both China and the United States, the most frequent clinical use of acupuncture—and the most conclusive evidence for its efﬁcacy—is in the treatment of pain.4 For example, there is research demonstrating its efﬁcacy in alleviating dental pain. To some extent, acupuncture also appears to relieve muscle spasm, low back pain, headaches, trigeminal neuralgia, osteoarthritis, ﬁbromyalgia, and abdominal pain. Other types of pain—for example, pain with a mental rather than an organic cause—are less amenable to acupuncture.

We should not be surprised at acupuncture’s effectiveness in reducing pain, since opioids appear to be at the heart of our response to this form of acupuncture treatment. Acupuncture’s inﬂuence on pain seems far more widely distributed throughout the brain (in the cortex, subcortical regions, and spinal cord) than its inﬂuence on the cardiovascular system, which seems to be mediated by relatively restricted areas of the brain.

In 1979, an interregional seminar of the World Health Organization (WHO) identiﬁed several diseases and conditions—in addition to pain—for which there is evidence of some efﬁcacy with acupuncture.5 These are inﬂammation and infection, dysfunction of the autonomic nervous system, central and peripheral neurological diseases, asthma, tinnitus, drug abuse, mood and behavior disorders, and cardiovascular disease. Again, this seems logical because of acupuncture’s inﬂuence on the central and peripheral nervous systems. At this time, however, there is relatively little information from studies conducted according to rigorous Western medical standards—such as randomized controlled trials—that demonstrates acupuncture’s superiority to placebo in treating most diseases other than pain. Currently, a clinical trial of acupuncture for treating hypertension is being conducted in Boston. Other clinical trials of acupuncture’s effect on cardiac arrhythmias and ischemia are needed.

ACUPUNCTURE OR PLACEBO?

Acupuncture is widely used for many conditions, with such conﬁdence by millions of patients, so why is it difﬁcult to prove that it works? One problem is the placebo effect. In testing any treatment, of course, we must deal with this possibility, but it is especially tricky when it comes to acupuncture. Taken together, Western medical trials of acupuncture have shown a relatively narrow window of superiority compared to placebo (approximately 70 percent of individuals reported favorable results on acupuncture versus about 40 percent on placebos). Why should this be surprising? The opioid system may be a major underlying mechanism in both placebo- and acupuncture-related responses. Clinical studies examining the response to acupuncture must be carefully controlled to distinguish the differences.

Researchers argue over alternative procedures that should be used to eliminate the potential confusion.6 In place of the standard sugar pill, possibilities include tapping but not penetrating the skin, performing acupuncture outside the meridian, or needling at an acupoint along a meridian that is not believed to be effective for the condition. Most people who have experienced acupuncture will not be fooled by simply having the skin tapped, so an adequate replacement would most likely be acupuncture at an unrelated area. Among the sensations induced by acupuncture, the most common is what is called deQi, which most lay people would describe as tingling, heaviness, dull pressure, or mild pain, and which most clinicians would refer to as a radiating paresthesia. It is likely that there would be differences in perception between stimulating a major neural pathway and stimulating outside it. This has led many researchers to conclude that the most appropriate sham control for acupuncture, which should be included in every trial of acupuncture’s clinical efﬁcacy, is stimulation along a meridian at an acupoint that does not cause a clinical response. But this raises another important issue in evaluating acupuncture: acupoint speciﬁcity.

Point speciﬁcity is the term that many acupuncturists use to refer to the ability of stimulating a particular acupuncture point to bring about a speciﬁc response. For example, in cardiovascular disease, the Neiguan (PE 6) and Zusanli (ST 36) acupoints, located along the pericardial and stomach meridians and lying over the median and deep peroneal nerves, respectively, are thought to be important.7 Other evidence from functional magnetic resonance imaging (fMRI) of the brain suggests that stimulating an acupoint along the urinary bladder meridian (BL 67) that overlies the sural nerve in the foot and small toe, which is considered effective in treating eye disturbances, can increase metabolism in the visual cortex.8

Indeed, point speciﬁcity is integral to TCM. As noted, stimulation of a particular acupoint or group of acupoints is typically used to restore the energy balance of an organ that is in either deﬁciency or excess. Unfortunately, there have been relatively few studies demonstrating point speciﬁcity and, although textbooks on acupuncture deﬁne those acupoints that produce important clinical responses, there is little consistency among acupuncturists in their selection of acupoints for speciﬁc diseases. Also, some basic concepts of point speciﬁcity are essentially unsupported by any valid results from well-constructed studies. For example, auricular acupuncture— the practice of performing acupuncture in the external ear, a technique invented in France just a few decades ago—purportedly targets virtually every organ in the body. But despite its widespread use, its superiority to placebo has not been adequately documented.

We urgently need further studies of point speciﬁcity to deﬁne the superiority of acupuncture over placebo and to ﬁnd out which sham procedure is the best research control.

TREATMENT OF CARDIOVASCULAR DISEASE

Amid all these reservations and caveats, there is an active area of investigation now yielding evidence that acupuncture may be effective in treating cardiovascular disease. Experiments by Peng Li and Tai Yao in animal models indicate that acupuncture can lower blood pressure, whether the high blood pressure is due to genetics, stress, or catecholamines.9 Bruce Pomeroy and many others have shown that the production of opioid peptides appears to be the major mechanism at work.10 Scientists have used low-frequency, low-intensity (and therefore not painful) electroacupuncture at the Neiguan and Zusanli acupoints to treat hypertension successfully.

A few small clinical studies also suggest that acupuncture can lower blood pressure somewhat, at least, in patients with essential hypertension (high blood pressure with no known organic cause). In May 2000, a workshop sponsored by the National Heart, Lung, and Blood Institute conﬁrmed that there is substantial experimental data on the neural-hormonal mechanisms underlying acupuncture’s effects, but also pointed out the paucity of major clinical trials deﬁning acupuncture’s role in treating hypertension and other forms of cardiovascular disease.11 Fortunately, large-scale, randomized, well-controlled studies, funded by the NIH Center for Alternative and Complementary Medicine, are under way, particularly in hypertension.

Interestingly, Dr. Li and his colleagues have shown that acupuncture also seems to be capable of increasing blood pressure in several types of low blood pressure, including shock caused by bleeding, drugs, or toxins from bacteria. Effective acupoints for treating this low blood pressure include Neiguan and Zusanli—the same ones used to treat high blood pressure. Although low-frequency, low-current EA has commonly been used, high-frequency, high-current EA is also effective, presumably because it stimulates the nerves that cause excitatory cardiovascular reﬂexes. The primary neurotransmitter involved in this response appears to be acetylcholine acting in the hypothalamus, midbrain, and medulla.

Experiments in my laboratory and others have shown that acupuncture may reduce myocardial ischemia (a deﬁciency of blood supply to the heart) and cardiac arrhythmias.12 Our recent studies conﬁrm that low-frequency, low-current EA at the Neiguan acupoint can be used to ameliorate myocardial ischemia via an opioid mechanism involving both endorphins and enkephalins in the medulla.13 Here acupuncture appears to blunt the demand for increased oxygen in the heart but not to dilate coronary blood vessels.

At least two U.S. and European laboratories have conﬁrmed that acupuncture reduces ischemia associated with exercise stress in patients with well-documented coronary artery disease.14 In this research, acupuncture was administered two to three times a week for 10 weeks, and the response was compared either to a tablet placebo or to sham acupuncture involving placement of needles outside meridians. The numbers of patients in these studies was small and the studies used multiple acupoints, some of which were not identiﬁed, so the results are not deﬁnitive.

Predictably, from its effect in lowering blood pressure, acupuncture may cause dilation or widening of the blood vessels (vasodilation), with possible beneﬁts in cardiovascular conditions associated with blood-vessel constriction. The WHO meeting mentioned earlier suggested some evidence that Raynaud’s syndrome (constriction of small arteries) and diabetic ulcers in the extremities resulting from low blood ﬂow may also respond to acupuncture, but there have been no well-controlled, randomized, double-blind studies.

ALTERNATIVES TO ACUPUNCTURE

There may be other ways to achieve the effects of traditional forms of acupuncture, acupressure, and moxibustion. Evidence shows that physical activity stimulating the nerves that carry impulses from the periphery of the body to the central nervous system can have an opioid-related, blood pressure-lowering effect.15 Exercise is known to stimulate two major groups of these so-called afferent (sensory) nerves (groups III and IV) and, in so doing, leads to what is known as the exercise pressor reflex: Following exercise of some duration, the blood pressure drops and remains for some time below the resting level. This effect depends upon an opioid-related mechanism in the spinal cord and brain.

An obvious analogy can be drawn between exercise, as a physiological form of afferent stimulation leading to decreased blood pressure, and acupuncture. They may not, however, be exactly equivalent; most forms of acupuncture, including manual and low-frequency, low-intensity EA, involve only slight motor activity. There is no increase in blood pressure during acupuncture. Then, too, exercise stimulates many systems—such as the lungs and skin—that are not inﬂuenced as much by acupuncture. In acupuncture and exercise, different groups of afferent nerve ﬁbers, and different patterns of response, may lead to different activation of the central nervous system.

A form of nerve stimulation called transcutaneous electrical nerve stimulation (TENS) has been put forward as a noninvasive substitute for electroacupuncture.16 TENS has been used successfully to treat chronic pain, perhaps by limiting the transmission of pain signals at the level of the spinal cord.17 TENS mildly inhibits the blood pressure-lowering response to exercise and has been used to treat patients with ischemic heart disease. Used brieﬂy or over the long term, TENS appears to reduce spontaneous or pacing-induced angina.

TENS does not inhibit angina and sympathetic activity through an opioid mechanism, possibly because TENS is administered at high frequency, with high currents that frequently cause pain. Additional well-designed studies are needed to compare TENS with acupuncture.

WHAT PATIENTS ARE SEEKING

Acupuncture is here to stay. Along with other forms of complementary medicine, acupuncture is claiming more and more of our resources for health care. This is quite simply because patients in increasing numbers demand it. But why, when we have so little information about its clinical efﬁcacy? Part of the answer can be found in changing attitudes toward the acceptance of alternative treatments. People are requesting referrals to acupuncturists even when not prompted by their family or physician.

Let me suggest three directions in which to look for an answer. First, patients are not satisﬁed with traditional Western treatments, which often have powerful side effects and yet fail to bring about a complete cure. Second, patients are participating more and more in decisions about their own health care. They are inﬂuenced by articles, advertisements, Web sites, and suggestions from friends and neighbors—and frequently these sources promote alternative health care. Finally, many patients want treatments that evoke the natural, self-healing processes in all of us. Why not use acupuncture to call forth a chemical already present in your body, if that chemical will treat your condition, instead of taking a drug fraught with unpredictable side effects?

LOOKING AHEAD

If acupuncture is with us for the long haul, how can we be sure that it is used wisely?

Many questions remain, after all, about how it works. The NIH Consensus Conference published in late 1997 urged greater clarity in deﬁning how acupuncture acts.18 Research has begun to show that the endogenous opioid system is integral to acupuncture’s action in pain and possibly several cardiovascular conditions, and that many regions of the hypothalamus, midbrain, and medulla are sites of integration where acupuncture exerts its inﬂuence on the cardiovascular system. The roles of neurotransmitters, including acetylcholine, amino butyric acid, serotonin, nitric acid, and nociceptin, among others, also need to be examined. We need to understand how they work both in areas of the brain known to be inﬂuenced by acupuncture and in areas still in question.

A big unanswered question is how each of these neurotransmitters acts in conjunction with the better-known neurotransmitters, such as glutamate and various glutamate subtype receptors, that seem to be responsible for the hindbrain’s neurotransmission of autonomic responses that govern the cardiovascular system. Do the neurotransmitters released by acupuncture act as neuromodulators, modifying the action of the primary neurotransmitter? Or do they serve as an alternative neurotransmitter?

Even a relatively brief application (1530 minutes) of acupuncture can inhibit pain for hours. What is the cellular basis of this prolonged action? What about the apparent contradiction between the speciﬁcity of acupoints in textbooks and the observation that most acupuncturists needle a combination of points that experience has shown them will work? Can we determine what is the best point, or combination of points, for treating speciﬁc diseases?

A major challenge is to identify the conditions most helped by acupuncture. As I have said, we know clinically that acupuncture reduces certain kinds of pain and that we have good evidence from experimental models now to suggest that it may be effective in treating certain cardiovascular disorders. But we have much less evidence, beyond some small pilot clinical studies, demonstrating its usefulness in treating other cardiovascular problems such as hypertension, angina, and cardiac arrhythmias. For conditions such as asthma, infection, or mood disorders, the evidence is slimmer still. Carefully constructed studies, in accordance with the best practices of Western medical science, are clearly needed. Only then will the medical and scientiﬁc fraternities be convinced that acupuncture is a genuinely effective medical tool.

Mayer DJ: Acupuncture: an evidence-based review of the clinical literature. Annual Review of Medicine 2000;51:49-63. Pomeranz B: Scientific research into acupuncture for the relief of pain. Journal of Alternative and Complementary Medicine. 1996;2:53-60.

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About Cerebrum

Bill Glovin, editor Carolyn Asbury, Ph.D., consultant

Scientific Advisory Board Joseph T. Coyle, M.D., Harvard Medical School Kay Redfield Jamison, Ph.D., The Johns Hopkins University School of Medicine Pierre J. Magistretti, M.D., Ph.D., University of Lausanne Medical School and Hospital Robert Malenka, M.D., Ph.D., Stanford University School of Medicine Bruce S. McEwen, Ph.D., The Rockefeller University Donald Price, M.D., The Johns Hopkins University School of Medicine